The triplication of chromosome 21 results in mental retardation for children with Down syndrome (DS). Although the brain is somewhat compromised at birth, much of the abnormal development associated with DS occurs in postnatal developing structures, such as the hippocampus. Indeed, children with DS have particular difficulty with hippocampal-mediated spatial tasks. In addition to childhood learning delays, individuals with DS are subjected to the additional cognitive stress of early Alzheimer's disease. Previous work in the fetal lethal Trisomy 16 DS mouse model demonstrated diploid cells in Ts16-diploid chimeric mice prevent the lethality and the chimeric mice survive up to one year. Neural progenitor cells (NPC) have been used to treat diseases with a global pathology, as is seen in DS. NPC can migrate, differentiate into glia and neurons, and secrete growth factors to promote the survival of and provide guidance cues for endogenous neurons. This has lead to the hypothesis that NPC may be useful as a very early treatment of DS and model a more normal neuro-anatomical development during the critical early learning period. The proposed longitudinal study will examine the effects of NPC transplantation on cognition and neuroanatomy in the DS mouse model, the Ts65Dn mouse. Aim 1: Determine if murine NPC (mNPC) transplanted into the hippocampus can alleviate the early and late cognitive dysfunction in Ts65Dn mice. Postnatal day 2 mice will be bilaterally implanted with C17.2 mNPC into the hippocampus. Behavior testing will assess cognitive function at 2, 6, and 12 months of age. Three different behavior tests will be employed to elicit the function of specific components of the learning and memory pathway. Aim 2: Determine the level of mNPC survival and their fate over the lifetime of the transplanted mice. A subset of animals will be analyzed immunohisto- chemically after each round of behavior testing. mNPC survival, migration, and differentiation will be assessed, with higher mNPC concentrations expected in areas involved in learning and memory (the hippocampus, medial septum, and prelimbic prefrontal cortex). Aim 3: Investigate alterations in presynaptic densities and dendritic morphology in the hippocampus and prefrontal cortex. Golgi staining and immuno- histochemistry against synaptophysin will be used to examine dendritic morphology and presynaptic density, respectively. Results from Aims 2 and 3 will be correlated with behavioral research obtained in Aim 1. Public Health Relevance: The use of NPC at an early age may be able to increase cognitive function and make learning easier for children with DS. Furthermore, allowing the brain to make the correct initial connections may prevent the early onset of Alzheimer's disease that people with Down syndrome face.